Azepans and methods for making and using same

ABSTRACT

Disclosed are compounds having the formula: 
     
       
         
         
             
             
         
       
     
     wherein Z 1  is an alkylene moiety; Q is a carboxylic acid derivative; and R 1  and R 2  are the same or different and are selected from the group consisting of alkyl, aryl, alkylcarbonyl, arylcarbonyl, hydroxycarbonyl, and alkoxycarbonyl or R 1  and R 2 , taken together with the nitrogen atom to which they are bound, form a ring. Also disclosed are compounds having the formula: 
     
       
         
         
             
             
         
       
     
     wherein Z 1  is an alkylene moiety; Q is a carboxylic acid derivative; and R 13  is selected from the group consisting of alkyl and aryl. The compounds can be used to modulate cell proliferation and/or apoptosis, for example, in the treatment of cancers and other proliferative diseases, disorders, and conditions.

The present application claims the benefit of U.S. Provisional PatentApplication Ser. No. 60/873,183, filed Dec. 6, 2006, which provisionalpatent application is hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates generally to azepans and, moreparticularly, to 2-oxo-azepans that are substituted in the 1- and3-positions.

BACKGROUND OF THE INVENTION

Normal tissues in the body are formed either by cells that have reacheda terminally differentiated state and no longer divide or by cells thatdie after a period of time and are replaced from a pool of dividingcells. For example, nervous tissue is formed early in development andthe cells of the nervous system reach a terminally differentiated statesoon after birth. In contrast, the body has a number of self renewingtissues such as skin, gut, bone marrow and sex organs which undergo abalanced flux of cell birth and death. This flux, which results in theproduction of 50 to 70 billion cells per day in an average adult andamounting to a mass of cells equivalent to an entire body weight over ayears time, is balanced by the regulated eradication of an equivalentnumber of cells. In self-renewing tissues the eradication is maintained,in part, due to the process of programmed cell death, known asapoptosis, in which the cells are genetically “programmed” to die aftera certain period of time.

Apoptosis is particularly prominent during the development of anorganism, where cells that perform transitory functions are programmedto die after their function no longer is required. In addition,apoptosis can occur in cells that have undergone major geneticalterations, thus providing the organism with a means to rid itself ofdefective and potentially cancer forming cells. Apoptosis also can beinduced due to exposure of an organism to various external stimuli,including, for example, bacterial toxins, ethanol, and ultravioletradiation. Chemotherapeutic agents for treating cancer also are potentinducers of apoptosis.

The regulation of programmed cell death is a complex process involvingnumerous pathways and, on occasion, defects occur in the regulation ofprogrammed cell death. Given the critical role of this process inmaintaining a steady-state number of cells in a tissue or in maintainingthe appropriate cells during development of an organism, defects inprogrammed cell death often are associated with pathologic conditions.It is estimated that either too little or too much cell death isinvolved in over half of the diseases for which adequate therapies donot currently exist.

Various disease states occur due to aberrant regulation of programmedcell death in an organism. For example, defects that result in adecreased level of apoptosis in a tissue as compared to the normal levelrequired to maintain the steady-state of the tissue can result in anincreased number of cells in the tissue. Such a mechanism of increasingcell numbers has been identified in various cancers, where the formationof a tumor occurs not because the cancer cells necessarily are dividingmore rapidly than their normal counterparts, but because the cells arenot dying at their normal rate.

For these and other reasons, a need exists for agents capable ofmodulating programmed cell death pathways. The present invention isdirected, in part, to addressing this need.

SUMMARY OF THE INVENTION

The present invention relates to a compound having the formula:

wherein Z¹ is an alkylene moiety; Q is a carboxylic acid derivative; andR¹ and R² are the same or different and are selected from the groupconsisting of alkyl, aryl, alkylcarbonyl, arylcarbonyl, hydroxycarbonyl,and alkoxycarbonyl or R¹ and R², taken together with the nitrogen atomto which they are bound, form a ring.

The present invention relates to a compound having the formula:

wherein Z¹ is an alkylene moiety; Q is a carboxylic acid derivative; andR¹³ is selected from the group consisting of alkyl and aryl.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1B are bar graphs showing the effect of a compound of thepresent invention on PC-3 prostate cancer cell growth inhibition after 3days treatment (FIG. 1A) and 5 days treatment (FIG. 1B).

FIGS. 2A-2B are bar graphs showing the effect of a compound of thepresent invention on 2008 ovarian cancer cell growth inhibition after 3days treatment (FIG. 2A) and 5 days treatment (FIG. 2B).

FIGS. 3A-3B are bar graphs showing the effect of a compound of thepresent invention on A549 lung cancer cell growth inhibition after 3days treatment (FIG. 3A) and 5 days treatment (FIG. 3B).

FIG. 4A is an image of a series of stained 6-well plates showing theeffect of various concentrations (1 μM, 5 μM, 10 μM, and 20 μM) of acompound of the present invention and a control (no compound of thepresent invention) on colony formation for P11/2008 ovarian cancercells, A549 lung cancer cells, HCT116 colon cancer cells, and PC-3prostate cancer cells. FIGS. 4B-4E are bar graphs showing quantitativeresults derived from the stained 6-well plates shown in FIG. 4A forP11/2008 ovarian cancer cells (FIG. 4B), A549 lung cancer cells (FIG.4C), HCT116 colon cancer cells (FIG. 4D), and PC-3 prostate cancer cells(FIG. 4E).

FIGS. 5A-5E are images showing the effect of a compound of the presentinvention on cancer cell morphology. FIGS. 5C-5E are images of MCF-7breast cancer cells after 3 days' treatment with 20 μM of a compound ofthe present invention, and FIGS. 5A-5B are control images (no compoundof the present invention).

FIGS. 6A-6C are a series of histograms showing the effect of a compoundof the present invention (at three concentrations (1 μM, 5 μM, and 10μM) and control (no compound of the present invention)) on the cellcycle distribution after 1 day, 2 days, and 3 days treatment for 2008ovarian cancer cells (FIG. 6A), lung cancer cells (FIG. 6B), and PC-3prostate cancer cells (FIG. 6C).

FIG. 7 is a bar graph showing the effects of p53 and p21 status inHCT116 colon cancer cells on cell growth inhibition mediated by acompound of the present invention.

FIG. 8 is a bar graph showing the effect of a compound of the presentinvention on the cytoplasmic histone-associated DNA fragmentation at 48hours after treatment in HCT116 colon cancer cells at 2 concentrations(10 μM and 20 μM) compared with control (no compound of the presentinvention).

FIG. 9 is an image of a series of Western blots indicating that acompound of the present invention downregulates survivin expression andactivates caspases 9 and 3 in HCT116 colon cancer cells at 48 hoursafter treatment.

FIG. 10 is a bar graph showing that survivin promoter activity in MCF-7breast cancer cells decreases with increasing concentration of acompound of the present invention. *p<0.05, **p<0.01.

FIG. 11 is an image of a series of Western blots indicating that, whilea compound of the present invention downregulates both survivin andBcl-2 expression in 2008 ovarian cancer cells, it has no effect on theexpression of XIAP in 2008 ovarian cancer cells.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, “alkyl” is meant to include linear alkyls, branchedalkyls, and cycloalkyls, each of which can be substituted orunsubstituted. “Alkyl” is also meant to include lower linear alkyls(e.g., C1-C6 linear alkyls), such as methyl, ethyl, n-propyl, n-butyl,n-pentyl, and n-hexyl; lower branched alkyls (e.g., C3-C8 branchedalkyls), such as isopropyl, t-butyl, 1-methylpropyl, 2-methylpropyl,1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl,1,1-dimethylpropyl, 2,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl,1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl,3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 2-methyl-2-ethylpropyl,2-methyl-1-ethylpropyl, and the like; and lower cycloalkyls (e.g., C3-C8cycloalkyls), such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,and the like. “Alkyl”, as used herein, is meant to include unsubstitutedalkyls, such as those set forth above, in which no atoms other thancarbon and hydrogen are present. “Alkyl”, as used herein, is also meantto include substituted alkyls. Suitable substituents include aryl groups(which may themselves be substituted), heterocyclic rings (saturated orunsaturated and optionally substituted), alkoxy groups (which is meantto include aryloxy groups (e.g., phenoxy groups)), amine groups (e.g.,disubstituted with aryl or alkyl groups), carboxylic acid derivatives(e.g., carboxylic acid esters, amides, etc.), halogen atoms (e.g., Cl,Br, and I), and the like. Further, alkyl groups bearing one or morealkenyl or alkynyl substituents (e.g., a methyl group itself substitutedwith a prop-1-en-1-yl group to produce a but-2-en-1-yl substituent) ismeant to be included in the meaning of “alkyl”. Other suitablesubstituents include hydroxy groups and protected hydroxy groups (e.g.,an acyloxy group, such at an acetoxy group; a silyl ether group, such asa trimethylsilyl (“TMS”) ether group and a tert-butyldimethylsilyl(“TBS”) ether group).

As used herein, “alkylene” refers to a bivalent alkyl group, where alkylhas the meaning given above. Linear, branched, and cyclic alkylenes, aswell as examples thereof, are defined in similar fashion with referenceto their corresponding alkyl group. Examples of alkylenes includeeth-1,1-diyl (i.e., —CH(CH₃)—), eth-1,2-diyl (i.e., —CH₂CH₂—),prop-1,1-diyl (i.e., —CH(CH₂CH₃)—), prop-1,2-diyl (i.e., —CH₂—CH(CH₃)—),prop-1,3-diyl (i.e., —CH₂CH₂CH₂—), prop-2,2-diyl (e.g. —C(CH₃)₂—),cycloprop-1,1-diyl, cycloprop-1,2-diyl, cyclopent-1,1-diyl,cyclopent-1,2-diyl, cyclopent-1,3-diyl, cyclohex-1,1-diyl,cyclohex-1,2-diyl, cyclohex-1,3-diyl, cyclohex-1,4-diyl,but-2-en-1,1-diyl, cyclohex-1,3-diyl, but-2-en-1,4-diyl,but-2-en-1,2-diyl, but-2-en-1,3-diyl, but-2-en-2,3-diyl. Also includedin the meaning of the term “alkylene” are compounds having the formula—R′—R″—, where —R′ represents a linear or branched alkyl group and R″—represents a cycloalkyl group.

As used herein, “alkoxy” is meant to include groups having the formula—O—R, where R is an alkyl or aryl group. They include methoxy, ethoxy,propoxy, phenoxy, 4-methylphenoxy, and the like.

As used herein, “aryl” is meant to include aromatic rings, for example,aromatic rings having from 4 to 12 members, such as phenyl rings. Thesearomatic rings can optionally contain one or more heteroatoms (e.g., oneor more of N, O, and S), and, thus, “aryl”, as used herein, is meant toinclude heteroaryl moieties, such as pyridyl rings, pyridiminyl rings,and furanyl rings. The aromatic rings can be optionally substituted.“Aryl” is also meant to include aromatic rings to which are fused one ormore other aryl rings or non-aryl rings. For example, naphthyl groups,indole groups, isoindole groups, and 5,6,7,8-tetrahydro-2-naphthylgroups (each of which can be optionally substituted) are aryl groups forthe purposes of the present application. As indicated above, the arylrings can be optionally substituted. Suitable substituents include alkylgroups (which can optionally be substituted), other aryl groups (whichmay themselves be substituted), heterocyclic rings (saturated orunsaturated), alkoxy groups (which is meant to include aryloxy groups(e.g., phenoxy groups)), amine groups (e.g., disubstituted with aryl oralkyl groups), carboxylic acid groups, carboxylic acid derivatives(e.g., carboxylic acid esters, amides, etc.), halogen atoms (e.g., Cl,Br, and I), and the like.

As used herein, “ring” is meant to include homocyclic or heterocyclicrings. The homocyclic or heterocyclic ring can be saturated orunsaturated, aromatic or non-aromatic. The ring can be unsubstituted, orit can be substituted with one or more substituents. The substituentscan be saturated or unsaturated, aromatic or nonaromatic, and examplesof suitable substituents include those recited above in the discussionrelating to substituents on alkyl and aryl groups. Furthermore, two ormore ring substituents can combine to form another ring, so that “ring”,as used herein, is meant to include fused ring systems, and such fusedring systems can be saturated or unsaturated, aromatic or non-aromatic.In the case where the ring is saturated (i.e., in the case where each ofthe atoms making up the ring are joined by single bonds to other membersof the ring), the ring may optionally include unsaturated (aromatic ornonaromatic) or saturated substituents. Illustratively, the ring or ringsystem can contain 3, 4, 5, 6, 7, 8, 9, 10, or more members.

As used herein, “carboxylic acid derivative” is meant to include freecarboxylic acids, carboxylic acid salts, carboxylic acid esters,carboxylic acid amides, carboxylic acid chlorides and other carboxylicacid halides.

As used herein, “alkylcarbonyl”, “arylcarbonyl”, “hydroxycarbonyl”, and“alkoxycarbonyl” are meant to refer to moieties which have the followingformulae: —C(O)-alkyl, —C(O)-aryl, —C(O)-hydroxy, and —C(O)-alkoxy,respectively, wherein C(O) represents a carbonyl (C═O) group.

The present invention, in one aspect thereof, relates to a compoundhaving the formula:

wherein Z¹ is an alkylene moiety; Q is a carboxylic acid derivative; andR¹ and R² are the same or different and are selected from the groupconsisting of alkyl, aryl, alkylcarbonyl, arylcarbonyl, hydroxycarbonyl,and alkoxycarbonyl or R¹ and R², taken together with the nitrogen atomto which they are bound, form a ring.

As noted above, Z¹ is an alkylene moiety, examples of which includemethylene moieties, ethylene moieties, n-propylene moieties, n-butylenemoieties, and the like. These alkylene moieties can be substituted orunsubstituted. Suitable substituents include, for example, other alkylgroups (which can themselves be substituted, with, for example, arylgroups, as in the case where the alkylene moiety is substituted with abenzyl or other aralkyl group. Illustratively, Z¹ can have the formulaCH₂_(n) where n is an integer from 1 to 8, such as in the case where nis an integer from 1 to 6, an integer from 1 to 4, 1, 2, 3, 4, 5, 6, 7,8, etc. Illustratively, Z¹ can be a methylene, ethylene, n-propylene,n-butylene, or other alkylene moiety bearing one, two or threesubstituents, such as in the case where Z¹ is a methylene, ethylene,n-propylene, n-butylene, or other alkylene moiety bearing exactly onesubstituent (e.g., an arylmethyl substituent or other aralkylsubstituent), for example, on the carbon immediately adjacent to theazepan ring's nitrogen or on the carbon immediately adjacent to thecarboxylic acid derivative. In certain embodiments, Z¹ is a methylenemoiety, such as in the case where Z¹ has the formula —CH(R⁶)— or—C(R⁶)(R²⁰)— in which R⁶ and R²⁰ are the same or different and areselected from alkyl groups and aryl groups, for example, as in the casewhere Z¹ has the formula —CH(R⁶)— in which R⁶ is an alkyl group (e.g., abenzyl group or other aralkyl group).

In certain embodiments, Q is an amide. The amide nitrogen can beunsubstituted, monosubstituted, or disubstituted. Illustratively, theamide nitrogen can be substituted with one alkyl group, with two alkylgroups (which can be the same or different), with one aryl group, withtwo aryl groups (which can be the same or different), or with one alkylgroup and one aryl group; or the amide nitrogen can be incorporated intoa ring (e.g., a 4- to 8-membered ring). In certain embodiments Q has theformula —C(O)—N(R⁴)(R⁵) in which R⁴ and R⁵ are the same or different andare selected from the group consisting of hydrogen, alkyl, and aryl orin which R⁴ and R⁵, taken together with the nitrogen atom to which theyare bound, form a ring, such as a 5- or 6-membered ring).

In certain embodiments, the compound of the present invention has theformula:

in which Z¹ is an alkylene moiety (e.g., any of the alkylene moietiesdiscussed above) and in which R⁴ and R⁵ are the same or different andare selected from the group consisting of hydrogen, alkyl, and aryl orin which R⁴ and R⁵, taken together with the nitrogen atom to which theyare bound, form a ring. Illustratively, R⁴ can be a hydrogen, and R⁵ canbe an alkyl group (e.g., a benzyl group or other aralkyl group which canbe optionally substituted, for example, with substituents containing oneor more groups which increase the compound's water solubility, such asmorpholino groups, piperazine groups, acid groups (e.g., carboxylic acidgroups), polyethers, etc.).

Illustratively, the compound of the present invention can have theformula:

in which R⁴ and R⁵ are the same or different and are selected from thegroup consisting of hydrogen, alkyl, and aryl or in which R⁴ and R⁵,taken together with the nitrogen atom to which they are bound, form aring (for example, as discussed above) and in which n is an integer from1 to 4. By way of further illustration, such compounds can have theformula:

in which R⁶ is an alkyl group, such as an aralkyl group (e.g., a benzylgroup or other arylmethyl group). By way of still further illustration,such compounds can have the formula:

in which R⁷ is an aryl group; R⁸ is an aryl group; and Z² represents analkylene moiety (suitable examples of which include those discussedabove in the context of Z¹). By way of still further illustration, suchcompounds can have the formula:

in which R⁷ is an aryl group; R⁸ is an aryl group; and m is 0, 1, 2, or3. In certain embodiments, R⁷ is a phenyl group; in certain embodiments,R⁸ is a phenyl group; in certain embodiments, both R⁷ and R⁸ are phenylgroups; in certain embodiments, both R⁷ and R⁸ are phenyl groups, and R⁴is a hydrogen atom. In cases where both R⁷ and R⁸ are phenyl groups,these phenyl groups can be the same or they can be different. Examplesof suitable phenyl groups include unsubstituted phenyl group as well asphenyl group substituted in one, two, or more positions. Illustratively,R⁸ can be a phenyl group that is substituted (e.g., mono- ordi-substituted in the ortho and/or para positions) with one or moregroups that increase the compound's water solubility, such asmorpholino-containing groups, piperazine-containing groups,acid-containing groups (e.g., carboxylic acid-containing groups),polyether-containing groups, etc.), examples of which include groupshaving the formula —O-Z³-R²², in which Z³ represents an alkylene moiety(such as those discussed hereinabove) and in which R²² represents amorpholino group, piperazine group, carboxylic acid or other acid,polyether group, etc.).

In each of the above formulae, R¹ and R² can be the same or different,and they are selected from the group consisting of alkyl, aryl,alkylcarbonyl, arylcarbonyl, hydroxycarbonyl, and alkoxycarbonyl or R¹and R², taken together with the nitrogen atom to which they are bound,form a ring.

In certain embodiments, R¹ is an alkylcarbonyl, an arylcarbonyl, ahydroxycarbonyl, or an alkoxycarbonyl, such as in the case where thecompound of the present has the following formula:

wherein R⁹ is selected from the group consisting of alkyl, aryl, alkoxyand hydroxy, and R¹⁰ is selected from the group consisting of alkyl andaryl; or R⁹ and R¹⁰, taken together with the atoms to which they arebound, form a ring. In certain embodiments, R⁹ is an alkyl, such as analkyl having the formula —CH(NR²⁴R²⁵)R²⁶ wherein R²⁴ and R²⁵ are thesame or different and are selected from the group consisting ofhydrogen, alkyl, and aryl and R²⁶ is selected from the group consistingof hydrogen, alkyl, and aryl (e.g., as in the case where R²⁴ is H, R²⁵is H, and R²⁶ is an alkyl (e.g., a methyl, ethyl, propyl, or butylgroup, such a group having the formula —CH₃ or —CH₂CH₃). In certainembodiments, R⁹ and R¹⁰, taken together with the atoms to which they arebound, form a 5- to 10-membered ring, such as 5-membered or 6-memberedring (e.g., a 5- or 6-membered ring bearing a double-bonded oxygen onone of the carbon atoms adjacent to the nitrogen to which R¹⁰ is bonded,which 5- or 6-membered ring can be optionally have an aryl ring fusedthereto. In certain embodiments, R⁹ and R¹⁰, taken together with theatoms to which they are bound, form an indolyl or isoindolyl ring (e.g.,a 1-oxo-1,3-dihydro-isoindol-2-yl ring, which ring may be optionallysubstituted). In certain embodiments, R⁹ and R¹⁰ are selected such thatcompounds of the present invention have the formula:

wherein R¹¹ and R¹² are the same or different and are selected from thegroup consisting of hydrogen, alkyl, and aryl; and wherein A representsa fused aryl ring (e.g., a phenyl, a naphthyl, a pyridyl, etc.).Illustratively, suitable fused aryl rings include unsubstituted phenylrings, mono-substituted phenyl rings, disubstituted phenyl rings,unsubstituted naphthyl rings, mono-substituted naphthyl rings,disubstituted naphthyl rings, unsubstituted pyridyl rings,mono-substituted pyridyl rings, disubstituted pyridyl rings, etc. Incertain embodiments, R¹¹ is a hydrogen atom; in certain embodiments,both R¹¹ and R¹² are hydrogen atoms; in certain embodiments, both R¹¹and R¹² are hydrogen atoms and A represents a phenyl ring; and incertain embodiments, both R¹¹ and R¹² are hydrogen atoms and Arepresents an unsubstituted phenyl ring.

Illustratively, compounds of the present invention include those havingthe following formula:

as well as those having the following formula:

and those having the following formula:

wherein A, R¹¹, R¹², Z¹, n, R⁴, R⁵, and R⁶ have the meanings set forthabove. Suitable examples of A, R¹¹, R¹², n, R⁴, R⁵ and R⁶ include thoseset forth above. For example, in certain embodiments, A is a phenylgroup (e.g., an unsubstituted phenyl group); each of R¹¹ and R¹² is ahydrogen atom; and/or R⁶ is an aralkyl group (e.g., a benzyl group or adifferent arylmethyl group).

By way of further illustration, compounds of the present inventioninclude those having the following formula:

as well as those having the following formula:

wherein A, R¹¹, R¹², R⁴, R⁷, R⁸, m, and Z² have the meanings set forthabove. Suitable examples of A, R¹¹, R¹², R⁴, R⁷, R⁸, m, and Z² includethose set forth above. For example, in certain embodiments, A is aphenyl group (e.g., an unsubstituted phenyl group); each of R¹¹ and R¹²is a hydrogen atom; m is 1; R⁴ is an hydrogen atom; R⁷ is a phenyl group(e.g., an unsubstituted phenyl group); and/or R⁸ is a phenyl group(e.g., an unsubstituted phenyl group).

By way of still further illustration, compounds of the present inventioninclude those having the following formula:

wherein A is a fused aryl group (suitable examples of which arediscussed above), and wherein R²⁸ and R²⁹ are the same or different arylgroups (e.g., substituted or unsubstituted phenyl groups), such as inthe case where the compound has the following formula:

The present invention, in another aspect thereof, relates to compoundshaving the formula:

wherein Z¹ is an alkylene moiety; Q is a carboxylic acid derivative; andR¹³ is selected from the group consisting of alkyl and aryl.

Examples of suitable Z¹ alkylene moieties include those discussed above.For example, Z¹ can have the formula CH₂_(n) in which n is an integerfrom 1 to 4. Illustratively, Q can be an amide, suitable examples ofwhich include those discussed above.

In certain embodiments, the compound has the following formula:

wherein R¹⁵, R¹⁶, and R¹⁷ are the same or different and are selectedfrom the group consisting of hydrogen, alkyl, and aryl or in which twoor more of R¹⁵, R¹⁶, and R¹⁷ combine to form a ring. For example, incertain embodiments, R¹⁵, R¹⁶, and R¹⁷ are the same or different and areselected from the group consisting of hydrogen, alkyl, and aryl; incertain embodiments, R¹⁵ is a hydrogen, alkyl, or aryl, and R¹⁶ and R¹⁷combine to form a ring; and, in certain embodiments, R¹⁶ is a hydrogen,alkyl, or aryl, and R¹⁵ and R¹⁷ combine to form a ring.

By way of illustration, R¹⁵ can be an alkyl, for example, a methyl,ethyl, propyl, or butyl group, such a group having the formula —CH₃ or—CH₂CH₃. In certain embodiments, R¹⁵ is an ethyl group, such as asubstituted ethyl group (e.g., a mono-substituted, di-substituted, ortri-substituted ethyl group) or an unsubstituted ethyl group (having theformula —CH₂CH₃). In certain embodiments, R¹⁵ is an ethyl group (such asthose described above) and each of R¹⁶ and R¹⁷ is a hydrogen atom.

Illustratively, compounds of the present invention include those havingthe following formula:

as well as those having the following formula:

and those having the following formula:

wherein R¹⁵, R¹⁶, R¹⁷, Z¹, n, R⁴, R⁵, and R⁶ have the meanings set forthabove. Suitable examples of R¹⁵, R¹⁶, R¹⁷, Z¹, n, R⁴, R⁵, and R⁶ includethose set forth above. For example, in certain embodiments, R¹⁵ is analkyl (e.g., a methyl, ethyl, propyl, or butyl group); and/or each ofR¹⁶ and R¹⁷ is a hydrogen atom.

By way of further illustration, compounds of the present inventioninclude those having the following formula:

as well as those having the following formula:

wherein R¹⁵, R¹⁶, R¹⁷, R⁴, R⁷, R⁸, m, and Z² have the meanings set forthabove. Suitable examples of R¹⁵, R¹⁶, R¹⁷, R⁴, R⁷, R⁸, m, and Z² includethose set forth above. For example, in certain embodiments, R¹⁵ is analkyl (e.g., a methyl, ethyl, propyl, or butyl group); each of R¹⁶ andR¹⁷ is a hydrogen atom; m is 1; R⁴ is an hydrogen atom; R⁷ is a phenylgroup (e.g., an unsubstituted phenyl group); and/or R⁸ is a phenyl group(e.g., an unsubstituted phenyl group).

By way of still further illustration, compounds of the present inventioninclude those having the following formula:

R¹⁵ is an alkyl group) (suitable examples of which are discussed above),and wherein R²⁸ and R²⁹ are the same or different aryl groups (e.g.,substituted or unsubstituted phenyl groups), such as in the case wherethe compound has the following formula:

The aforementioned compounds of the present invention can be prepared byany suitable method, for example, by the methods described below, towhich methods the present invention also relates.

For example, compounds of the present invention can be made by aprocedure according to Scheme 1.

Briefly, phthalimide 12 can be prepared from commercially availableaminocaprolactam 10, for example, by reaction of 10 with phthalicanhydride. Phthalimide 12 can then be alkylated with a halogenated acidester (such as Br-Z¹-COOR³⁰ or I-Z¹-COOR³⁰, where R³⁰ is, for example,alkyl or aryl, such as in the case where R³⁰ is an ethyl group) followedby hydrolysis to obtain acid 14. Acid 14 can then be coupled withvarious amines to form amide 16. The phthalyl group can then be removedto form amine 18, and amine 18 can be alkylated to produce compound 20(a compound of the present invention).

Certain compounds of the present invention can be produced by other,perhaps more efficient methods.

For example, Scheme 2 shows a method for making a compound 22.

Briefly, referring to Scheme 2, aminocaprolactam 24 is converted toisoindole 26, using for example, the methodologies set forth in Jalil etal., “Synthesis of the Precursor of Anti-Inflammatory Agents byCross-Coupling Using Electrogenerated Highly Reactive Zinc,” Synthesis,2002:2681-2686; and Lawrence et al., “A Three-Component Coupling ProcessBased on Vicarious Nucleophilic Substitution (VNSAR)-AlkylationReactions: An Approach to Indoprofen and Derivatives,” J. Org. Chem.,67(2):457-464 (2002), which are hereby incorporated by reference.Isoindole 26 can then be alkylated with a halogenated acid ester (suchas Br-Z¹-COOR³¹ or I-Z¹-COOR³¹, where R³¹ is, for example, alkyl oraryl, such as in the case where R³¹ is an ethyl group) followed byhydrolysis to obtain acid 28. Acid 28 can then be coupled with variousamines to form compound 22. As one will appreciate, the nature of thehalogenated acid ester employed in the conversion of 26 to 28 willdepend on the desired identity of Z¹ in compound 22. For example, incases where Z¹ is a —CH₂— group, an alkyl bromoacetate can be employedin the conversion of 26 to 28.

By way of further illustration, Scheme 3 shows a method for making acompound 32.

Briefly, referring to Scheme 3, acid 36 can be prepared from compound 34using, for example, the methodologies described in Robl et al.,“Peptidomimetic Synthesis: A Novel, Highly Stereoselective Route toSubstituted Freidinger Lactams,” J. Am. Chem. Soc., 116:2348-2355(1994), which is hereby incorporated by reference. Acid 36 can then becoupled to benzyl amine (or, more generically, to other amines, such asthose having the formula HNR⁴R⁵, in which case the —NHBn group in Scheme3 would be replaced with the more generic —NR⁴R⁵) to form amide 38. Thephthalyl group can then be removed to form amine 40, and amine 40 can bealkylated to produce compound 32.

The compounds of the present invention and compounds produced by themethods of the present invention can be used in a variety of ways.

For example, compounds of the present invention in which Q is an amidecan be used to modulate cell proliferation and/or apoptosis, and arebelieved to be particularly useful in the treatment of proliferativediseases, disorders, and/or conditions, such as prostate, colon,ovarian, lung, breast, and other cancers.

In one aspect, compounds of the present invention can be used todecrease proliferation of cancer cells. In another aspect, compounds ofthe present invention can be used to induce apoptosis of cancer cells.The method includes contacting a sample which includes cancer cells witha compound of the present invention. The meaning of the terms“proliferation” and “apoptosis” are readily understood in the art.Illustrative methods for assaying for proliferation and apoptosis areprovided in the examples which follow. “Cancer cells”, as used herein,are meant to include cancerous epithelial cells, such as prostate cancercells, lung cancer cells, breast cancer cells, ovarian cancer cells, andcolon cancer cells. The methods of the present invention can bepracticed in vitro or in vivo.

For example, the method of the present invention can be used in vivo totreat cancers, such as prostate cancer, lung cancer, ovarian cancer,breast cancer, and colon cancer. In the case where the method of thepresent invention is carried out in vivo, for example, where the cancercells are present in a human subject, contacting can be carried out byadministering a therapeutically effective amount of a compound inaccordance with the present invention to the human subject, for example,by directly injecting a compound of the present invention into a tumor.Details with regard to administering the compounds are described below.

The compounds of the present invention can also be used in a method fortreating cancer, such as prostate cancer, lung cancer, breast, ovariancancer, colon cancer, or other cancers. As used in the context of thisaspect of the present invention, “treating” is meant to includepreventative treatments, for example in a subject at risk for cancer, aswell as treatments designed to slow, stop, or reverse progression of thecancer in subjects exhibiting clinical symptoms of cancer. The methodincludes administering, to the subject, a compound in accordance withthe present invention.

Suitable subjects include, for example mammals, such as rats, mice,cats, dogs, horses, monkeys, and humans. Suitable human subjectsinclude, for example, those which have previously been determined to beat risk of having prostate cancer, lung cancer, ovarian cancer, coloncancer, and/or breast cancer and those who have been diagnosed as havingsuch cancers. Preferably, the subject suffers from only one of thesetypes of cancers.

In subjects who are determined to be at risk of having cancer, theabove-identified compounds are administered to the subject, preferablyunder conditions effective to decrease proliferation and/or induceapoptosis of the cancer cells in the event that they develop. Suchpreventive (which is not used in the absolute 100% sense) therapy can beuseful in high risk individuals as long as the adverse side effects ofthe administration of these compounds are outweighed by the potentialbenefit of prevention.

It should be noted that the above-described methods for treating cancermay operate via a mechanism which involves inducing caspase activation(e.g., inducing caspase 3 and/or caspase 9 activation), inhibitingcolony formation, downregulating survivin expression and promoteractivity, arresting cancer cells in the G1 phase of the cell cycle,inhibition of Bcl-2 expression, inducing DNA fragmentation. However,such need not be the case, and this aspect of the present invention isnot, in any way, intended to be limited by the mechanism by which thecompounds of the present invention operate.

Any of the compounds of the present invention described above can beused in the treatment methods of the present invention. The compoundsmay be administered alone or in combination with compatible carriers asa composition. Compatible carriers include suitable pharmaceuticalcarriers or diluents. The diluent or carrier ingredients should beselected so that they do not diminish the therapeutic effects of thecompound.

The compositions herein may be made up in any suitable form appropriatefor the desired use. Examples of suitable dosage forms include oral,parenteral, or topical dosage forms.

Suitable dosage forms for oral use include tablets, dispersible powders,granules, capsules, suspensions, syrups, and elixirs. Inert diluents andcarriers for tablets include, for example, calcium carbonate, sodiumcarbonate, lactose, and talc. Tablets may also contain granulating anddisintegrating agents, such as starch and alginic acid; binding agents,such as starch, gelatin, and acacia; and lubricating agents, such asmagnesium stearate, stearic acid, and talc. Tablets may be uncoated ormay be coated by known techniques to delay disintegration andabsorption. Inert diluents and carriers which may be used in capsulesinclude, for example, calcium carbonate, calcium phosphate, and kaolin.Suspensions, syrups, and elixirs may contain conventional excipients,for example, methyl cellulose, tragacanth, sodium alginate; wettingagents, such as lecithin and polyoxyethylene stearate; andpreservatives, such as ethyl-p-hydroxybenzoate. Dosage forms for oraladministration can also be formulated as food preparations usingmaterials which are conventionally used in the food processing industry,such as proteins, sugars and other carbohydrates, extenders, fillers,preservatives, and the like.

Dosage forms suitable for parenteral administration include solutions,suspensions, dispersions, emulsions, and the like. They may also bemanufactured in the form of sterile solid compositions which can bedissolved or suspended in sterile injectable medium immediately beforeuse. They may contain suspending or dispersing agents known in the art.Examples of parenteral administration are intraventricular,intracerebral, intramuscular, intravenous, intraperitoneal, rectal, andsubcutaneous administration.

Suitable topical dosage forms include gels, creams, lotions, ointments,powders, aerosols and other conventional forms suitable for directapplication of medicaments to skin or mucous membranes. Topicalointments, pastes, creams, and gels can include, in addition to theactive compounds of the present invention, customary excipients, forexample animal and vegetable fats, waxes, paraffins, starch, tragacanth,cellulose derivatives, polyethylene glycols, silicones, bentonites,silicic acid, talc, and zinc oxide, or mixtures of these substances.Topical powders and sprays can include, in addition to the activecompounds of the present invention, the customary excipients, forexample lactose, talc, silicic acid, aluminium hydroxide, calciumsilicate and polyamide powder, or mixtures of these substances. Sprayscan additionally contain the conventional propellants, such aschlorofluorohydro-carbons.

In addition to the above, generally non-active components of theabove-described formulations, these formulations can include otheractive materials, particularly, actives which have been identified asuseful in the treatment of prostate, lung, breast, colon, ovariancancers and/or other cancers. These actives can be broad-basedanti-cancer agents, such that they also are useful in treating othertypes of cancers or they may be more specific, for example, in the casewhere the other active is useful for treating particular types ofadenocarcinomas. The other actives can also have non-anti-cancerpharmacological properties in addition to their anti-cancer properties.For example, the other actives can be XIAP antagonists; they can beinhibitors of XIAP expression; and/or they can have anti-inflammatoryproperties. Alternatively, the other actives can have none of theseproperties.

It will be appreciated that the actual preferred amount of compound ofthe present invention to be administered will vary according to theparticular compound being used, the particular composition formulated,and the mode of administration. Many factors that may modify the actionof the compound (e.g., body weight, sex, diet, time of administration,route of administration, rate of excretion, condition of the subject,drug combinations, and reaction sensitivities and severities) can betaken into account by those skilled in the art. Administration can becarried out continuously or periodically within the maximum tolerateddose. Optimal administration rates for a given set of conditions can beascertained by those skilled in the art using conventional dosageadministration tests.

It will be appreciated that certain compounds of the present inventionmay be more suitable for in vivo use than others. Illustratively,compounds of the present invention in which Q is a free carboxylic acidor a carboxylic acid halide may have minimal use in vivo, and compoundsof the present invention in which Q is a carboxylic acid ester may benon-optimal for in vivo use (owing, for example, to their susceptibilityto hydrolysis). However, such free acids, acid halides, and esters canbe used as intermediates, for example, in the preparation of thecorresponding amides.

In all of the formulae set forth in this document which contain one ormore chiral centers and which do not specify the stereochemistry of aparticular chiral center, such formulae are to be construed as referringeach of all possible stereochemistries. Thus, for example, where aformula is shown as having two chiral centers C*^(A) and C*^(B), theformula is meant to include (i) compounds in which each of C*^(A) andC*^(B) is entirely in the R configuration, (ii) compounds in which eachof C*^(A) and C*^(B) is entirely in the S configuration, (iii) compoundsin which C*^(A) is entirely in the S configuration and C*^(B) isentirely in the R configuration, (iv) compounds in which C*^(A) isentirely in the R configuration and of C*^(B) is entirely in the Sconfiguration, and (v) racemic and other mixtures of (i), (ii), (iii),and (iv). Illustratively, a compound having the formula:

is meant to include compounds having any one of the following formulae:

or mixtures thereof. By way of further illustration, a compound havingthe formula:

is meant to include compounds having any one of the following formulae:

and mixtures thereof.

The present invention is further illustrated by the followingnon-limiting examples.

EXAMPLES Example 1 Synthetic Procedures

Compounds 101 and 102 of the present invention were prepared inaccordance with the following Scheme A.

Briefly,(3R,6S,9aR)-3-benzyl-tetrahydro-6-(1,3-dioxo-isoindolin-2-yl)oxazolo[3,2-a]azepine-2,5(3H,6H)-dione(100) was prepared following the procedure set forth in Robl et al.,“Peptidomimetic Synthesis: A Novel, Highly Stereoselective Route toSubstituted Freidinger Lactams,” J. Am. Chem. Soc., 116:2348-2355(1994), which is hereby incorporated by reference. NMR was in agreementwith reported compound. ¹H-NMR (CDCl₃) δ −0.15 (m, 1H), 1.61 (m, 1H),1.71 (m, 1H), 1.85 (m, 2H), 2.57 (m, 1H), 3.25 (d, J=13.6 HZ, 1H), 3.58(dd, J=13.6, 6.4 Hz, 1H), 4.67 (d, J=11.6 Hz, 1H), 4.71 (d, J=6.0 HZ,1H), 5.57 (d, J=10.8 Hz, 1H), 7.23-7.42 (m, 5H), 7.73-7.98 (m, 2H).

2(R)-[2-Oxo-3(S)-(1-oxo-1,3-dihydro-isoindol-2-yl)-cycloheptyl]-3-phenyl-propionicacid (101) was prepared using the following procedure. Dione 101 (0.29g, 0.7 mmole) was dissolved in 5 ml of anhydrous dichloromethane(“DCM”). Triethylsilane (1.13 ml, 7.0 mmole) and titanium tetrachloride(1.4 ml, 1M in DCM) were then added, and the mixture was then stirred atroom temperature for 3 days. The reaction mixture was then quenched withwater and extracted with ethyl acetate. The organic layer was washedwith brine, dried with anhydrous sodium sulfate, and concentrated undervacuum. The residue was then purified using silica gel chromatographystarting with ethyl acetate as an eluant followed by 2% acetic acid inethyl acetate. The compound was collected as white solid (0.05 gm, 18%).¹H-NMR (CDCl₃) δ 1.46 (m, 1H), 1.68-1.97 (m, 5H), 2.90 (dd, J=16.0, 3.5Hz, 1H), 3.22 (m, 1H), 3.36-3.43 (m, 2H), 4.34-5.00 (abq, J=17.0 Hz,2H), 4.56 (m, 1H), 5.25 (d, J=11.0 Hz, 1H), 7.24-7.30 (m, 3H), 7.70 (t,J=7.5 Hz, 2H), 7.46 (t, J=7.5 Hz, 2H), 7.55 (t, J=7.5 Hz, 1H), 7.91 (d,J=7.5 Hz, 1H). MS (ES) m/z=391 (M-H)⁻.

N-Benzyl-2(R)-[2-oxo-3(S)-(1-oxo-1,3-dihydro-isoindol-2-yl)-cycloheptyl]-3-phenyl-propionamide(102) was synthesized from acid 101 and benzyl amine following thegeneral method for amide coupling. The product was obtained as a whitesolid. ¹H-NMR (CDCl₃) δ 1.25 (m, 1H), 1.67-1.95 (m, 5H), 2.98 (dd,J=14.5, 8.0 Hz, 1H), 3.37-3.50 (m, 2H), 3.60 (m, 1H), 4.25-4.45 (dabq,J=12.0, 15.0 Hz, 2H) 4.32-4.86 (abq, J=16.5 Hz, 2H), 5.23 (d, J=10.5 Hz,1H), 5.38 (t, J=8.0 Hz, 1H), 7.08 (d, J=7.5 Hz, 2H), 7.19-7.31 (m, 8H),7.47 (m, 2H), 7.54 (m, 1H), 7.86 (d, J=7.5 Hz, 1H). (HRMS, ESI): m/zfound 504.22595 [M+Na]⁺, C₃₀H₃₁N₃O₃Na requires 504.2258.

Example 2 Effects of Compound 102 on Cancer Cell Growth Inhibition

Functional screening of a drug library which included compound 102 byMTT assay following our previous protocol (Ling et al., “DifferentialExpression of Survivin-2B and Survivin-DeltaEx3 Is Inversely Associatedwith Disease Relapse and Patient Survival in Non-Small-Cell Lung Cancer(NSCLC),” Lung Cancer, 49:353-361 (2005), which is hereby incorporatedby reference) resulted in the hit of compound 102. Compound 102 showedsignificant cell growth inhibition property in several cancer celltypes, including PC-3 prostate cancer cells, 2008 ovarian cancer cells,and A549 lung cancer cells at initial concentration of 20 μM (data notshown). We then studied in detail the concentration-dependent effects ofcompound 102 on cell growth inhibition in various cancer cell types.FIGS. 1A and 1B show the results from PC-3 prostate cancer cells for 3and 5 days after compound 102 treatment. Similar results were alsoobtained in MCF-7 breast cancer cells. FIGS. 2A and 2B show the resultsfrom 2008 ovarian cancer cells for 3 and 5 days after compound 102treatment. FIGS. 3A and 3B show the results from A549 lung cancer cellsfor 3 and 5 days after compound 102 treatment.

From these results, we conclude that the compound 102 has broad andstrong inhibitory effects on various cancer cell growth. However, thetime course of its drug effect may vary among different cancer celltypes.

Example 3 Effects of Compound 102 on Cancer Cell Colony Formation

Next, we tested the inhibitory effect of compound 102 on cancer cellcolony formation for various cancer cells (P11/208, A549, HCT116, andPC-3). Two hundred cells were seeded in each well of 6-well plates.Twenty-four hours after seeding, the cells were treated one time withcompound 102 at various concentrations (0 μM, 20 μM, 10 μM, 5 μM, and 1μM). The cells were then cultured for two weeks and stained with crystalviolet to detect cancer colony formation. The results are presented inFIGS. 4A-4E. FIG. 4A is an image of the stained 6-well plates. FIG. 4B(P11/2008), FIG. 4C (A549), FIG. 4D (HCT116), and FIG. 4E (PC-3) are bargraphs showing quantitative results derived from the stained 6-wellplates shown in FIG. 4A.

Example 4 Effects of Compound 102 on Cancer Cell Morphological Changes

The effects of compound 102 on cancer cell morphological changesappeared to be very interesting. For example, treatment of variouscancer cells with compound 102 at 20 μM for 24 hours did not showsignificantly morphological changes. The morphological changes beganafter 24-hour treatment, and dramatic changes were observed after72-hour treatment. The results from the MCF-7 breast cancer cells after3 days' treatment are shown in FIGS. 5A-5E. FIGS. 5C-5E are three imagesof MCF-7 breast cancer cells treated for 3 days with 20 μM of compound102. FIGS. 5A-5B are control images (no compound 102). Similar resultswere also obtained in other cancer cells. Here, we would like to pointout that the slow effect of compound 102 on cell morphological changesand cancer cell growth inhibition in certain cell type suggest thatthere is a unique drug action mechanism involved in the effects ofcompound 102 action.

Example 5 Effects of Compound 102 on Cancer Cell Cycle Control

We next studied the effects of compound 102 on cancer cell cyclecontrol. We found that compound 102 effectively arrests cancer cells inG1 phase of the cell cycle as shown in FIGS. 6A-6C. FIGS. 6A-6C show theeffect of compound 102 (at three concentrations (1 μM, 5 μM, and 10 μM)and control (no compound 102)) on the cell cycle distribution after 1day, 2 days, and 3 days treatment for 2008 ovarian cancer cells (FIG.6A), lung cancer cells (FIG. 6B), and PC-3 prostate cancer cells (FIG.6C). This observation is consistent with the observation below (Example6) that p53 and p21 status is associated with cancer cell growthinhibition induced by compound 102.

Example 6 Effects of p53 and p21 Status in HCT116 Colon Cancer Cells onCell Growth Inhibition Mediated by Compound 102

Since the data suggested that compound 102 could induce cancer cell G1arrest, we examined the effects of p53 and p21 status in HCT116 coloncancer cells on cell growth inhibition mediated by compound 102. Theresults are presented in FIG. 7 and indicate that, consistent with thefactor that compound 102 promotes cancer cells G1 arrest, the efficacyof compound 102 on cancer cell growth inhibition is associated with bothp53 and p21 gene status.

Example 7 Effect of Compound 102 on DNA Fragmentation and CaspaseActivation

To test whether compound 102 induces apoptotic cancer cell death, weperformed DNA fragmentation cell death ELISA assays (Roche) and Westernblots to test activation of caspases. FIG. 8 shows the effect ofcompound 102 on the cytoplasmic histone-associated DNA fragmentation at48 hours after compound 102 treatment in HCT116 colon cancer cells at 2concentrations (10 μM and 20 μM) compared with control (no compound102). FIG. 8 demonstrates that compound 102 strikingly enhances cell DNAfragmentation, a hallmark of apoptotic cell death. FIG. 9 shows seriesof Western blots indicating that compound 102 downregulates survivinexpression and activates caspases 9 and 3 in HCT116 colon cancer cellsat 48 hours after compound 102 treatment.

Example 8 Effect of Compound 102 on Survivin Expression, PromoterActivity and XIAP Expression

As discussed in Example 7, FIG. 9 showed that activation of caspases 9and 3 induced by compound 102 is associated with downregulation ofsurvivin expression. Intriguingly, we further found that compound 102 isable to downregulate survivin promoter activity. Briefly, a survivinpromoter-luciferase construct (pLuc-6309) was transfected into MCF-7breast cancer cells. Transfected cells were treated with compound 102(at 3 concentrations (5 μM, 10 μM, and 20 μM)) and control (no compound102) for 24 hours at 12 hours after transfection. A luciferase activityassay was then performed using the Dual Luciferase Reporter Assay System(Promega). The results, presented in FIG. 10, show that survivinpromoter activity decreases with increasing compound 102 concentration.These observations suggest the possibility that downregulation ofsurvivin expression and promoter activity may be required for apoptosisinduction.

To test the specificity of compound 102 on survivin inhibition, weperformed Western blots to determine the effect of compound 102 on Bcl-2expression and on XIAP expression. The results, presented in FIG. 11,show that while compound 102 downregulates both survivin and Bcl-2expression in 2008 ovarian cancer cells, it has no effect on theexpression of XIAP in 2008 ovarian cancer cells.

Although the invention has been described in detail for the purpose ofillustration, it is understood that such detail is solely for thatpurpose, and variations can be made therein by those skilled in the artwithout departing from the spirit and scope of the invention which isdefined by the claims that are set forth below.

1. A compound having the formula:

wherein Z¹ is an alkylene moiety; Q is a carboxylic acid derivative; R¹and R² are the same or different and are selected from the groupconsisting of alkyl, aryl, alkylcarbonyl, arylcarbonyl, hydroxycarbonyl,and alkoxycarbonyl or R¹ and R², taken together with the nitrogen atomto which they are bound, form a ring.
 2. A compound according to claim1, wherein Z¹ is an alkylene moiety having the formula CH₂_(n) and nis an integer from 1 to
 4. 3. A compound according to claim 1, wherein Qis an amide.
 4. A compound according to claim 1 having the formula:

wherein n is an integer from 1 to 4; and wherein R⁴ and R⁵ are the sameor different and are selected from the group consisting of hydrogen,alkyl, and aryl or R⁴ and R⁵, taken together with the nitrogen atom towhich they are bound, form a ring.
 5. A compound according to claim 1having the formula:

wherein R⁴ and R⁵ are the same or different and are selected from thegroup consisting of hydrogen, alkyl, and aryl or R⁴ and R⁵, takentogether with the nitrogen atom to which they are bound, form a ring;and R⁶ is an alkyl group.
 6. A compound according to claim 5, wherein R⁶is a benzyl group.
 7. A compound according to claim 5 having theformula:

wherein R⁷ is an aryl group; R⁸ is an aryl group; and m is 0, 1, 2, or3.
 8. A compound according to claim 7, wherein m is 1; R⁴ is a hydrogenatom; R⁷ is a phenyl group; and R⁸ is a phenyl group.
 9. A compoundaccording to claim 1 having the formula:

wherein R⁹ is selected from the group consisting of alkyl, aryl, alkoxy,and hydroxy, and R¹⁰ is selected from the group consisting of alkyl andaryl; or R⁹ and R¹⁰, taken together with the atoms to which they arebound, form a ring.
 10. A compound according to claim 9, wherein R⁹ andR¹⁰, taken together with the atoms to which they are bound, form a ring.11. A compound according to claim 1 having the formula:

wherein R¹¹ and R¹² are the same or different and are selected from thegroup consisting of hydrogen, alkyl, and aryl; and wherein A representsa fused aryl ring.
 12. A compound according to claim 11, wherein Arepresents a phenyl ring, and wherein each of R¹¹ and R¹² is a hydrogenatom.
 13. A compound according to claim 1 having the formula:

wherein A represents a fused aryl ring; wherein R¹¹ and R¹² are the sameor different and are selected from the group consisting of hydrogen,alkyl, and aryl; wherein n is an integer from 1 to 4; and wherein R⁴ andR⁵ are the same or different and are selected from the group consistingof hydrogen, alkyl, and aryl or R⁴ and R⁵, taken together with thenitrogen atom to which they are bound, form a ring.
 14. A compoundaccording to claim 1 having the formula:

wherein A represents a fused aryl ring; wherein R¹¹ and R¹² are the sameor different and are selected from the group consisting of hydrogen,alkyl, and aryl; wherein R⁴ and R⁵ are the same or different and areselected from the group consisting of hydrogen, alkyl, and aryl or R⁴and R⁵, taken together with the nitrogen atom to which they are bound,form a ring; and R⁶ is an alkyl group.
 15. A compound according to claim14, wherein R⁶ is a benzyl group.
 16. A compound according to claim 1having the formula:

wherein A represents a fused aryl ring; wherein R¹¹ and R¹² are the sameor different and are selected from the group consisting of hydrogen,alkyl, and aryl; wherein R⁷ is an aryl group; R⁸ is an aryl group; and mis 0, 1, 2, or
 3. 17. A compound according to claim 16, wherein Arepresents a phenyl ring, and wherein each of R¹¹ and R¹² is a hydrogenatom.
 18. A compound according to claim 16, wherein A represents aphenyl ring, each of R¹¹ and R¹² is a hydrogen atom, m is 1, R⁴ is ahydrogen atom, R⁷ is a phenyl group, and R⁸ is a phenyl group.
 19. Acompound having the formula:

wherein Z¹ is an alkylene moiety; Q is a carboxylic acid derivative; andR¹³ is selected from the group consisting of alkyl and aryl.
 20. Acompound according to claim 19, wherein Z¹ is an alkylene moiety havingthe formula CH₂_(n) and n is an integer from 1 to
 4. 21. A compoundaccording to claim 19, wherein Q is an amide.
 22. A compound accordingto claim 19 having the formula:

wherein R¹⁵, R¹⁶, and R¹⁷ are the same or different and are selectedfrom the group consisting of hydrogen, alkyl, and aryl or in which twoor more of R¹⁵, R¹⁶, and R¹⁷ combine to form a ring.
 23. A compoundaccording to claim 22, wherein R¹⁵ is an alkyl group.
 24. A compoundaccording to claim 22, wherein R¹⁵ is an ethyl group.
 25. A compoundaccording to claim 22, wherein each of R¹⁶ and R¹⁷ is a hydrogen atomand R¹⁵ has the formula —CH₂CH₃.